Retinoic acid regulates erythropoietin production cooperatively with hypoxia-inducible factors in human iPSC-derived erythropoietin-producing cells

Sci Rep. 2021 Feb 16;11(1):3936. doi: 10.1038/s41598-021-83431-6.

Abstract

Erythropoietin (EPO) is a crucial hormone for erythropoiesis and produced by adult kidneys. Insufficient EPO production in chronic kidney disease (CKD) can cause renal anemia. Although hypoxia-inducible factors (HIFs) are known as a main regulator, the mechanisms of EPO production have not been fully elucidated. In this study, we aimed to examine the roles of retinoic acid (RA) in EPO production using EPO-producing cells derived from human induced pluripotent stem cells (hiPSC-EPO cells) that we previously established. RA augmented EPO production by hiPSC-EPO cells under hypoxia or by treatment with prolyl hydroxylase domain-containing protein (PHD) inhibitors that upregulate HIF signals. Combination treatment with RA and a PHD inhibitor improved renal anemia in vitamin A-depleted CKD model mice. Our findings using hiPSC-EPO cells and CKD model mice may contribute to clarifying the EPO production mechanism and developing efficient therapies for renal anemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / drug therapy*
  • Anemia / etiology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Drug Evaluation, Preclinical
  • Drug Therapy, Combination
  • Erythropoietin / biosynthesis*
  • Glycine / analogs & derivatives*
  • Glycine / therapeutic use
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • Induced Pluripotent Stem Cells
  • Isoquinolines / therapeutic use*
  • Kidney Diseases / complications
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Tretinoin / pharmacology
  • Tretinoin / therapeutic use*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoquinolines
  • Erythropoietin
  • endothelial PAS domain-containing protein 1
  • Tretinoin
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Glycine
  • roxadustat